Delta4, 6-androstadiene-9 halo compounds



2,83%,tid?

Patented May 2?, 1553 M -ANDROSTADIENE HALO COMPOUNDS Eugene J. Agnelloand Gerald D. Laubach, Jackson Heights, N. Y., assignors to Chas. Pfizer& Co., Inc., Brooklyn, N. Y., a corporation of Delaware No Drawing.Application April 1, 1957 Serial No. 649,657

2 Claims. (Cl. 260-3973) wherein R is hydrogen or CH R is fi-hydroxyl orketo; X is fluorine, chlorine, bromin or iodine; Z is R is hydrogen oracyl hydrocarbon containing up to ten carbonwatoms; and All: is an alkylgroup containing up to 1 four carbon atoms.

Suitable compounds for the preparaion of the valuable therapeutic agentsof this invention include those having the formula:

X R O: y

wherein R is hydrogen or CH These compounds are prepared by conventionalmeans from llfl-hydroxyl-androstene 3,17 dione or 1113 hydroxyl 19norandrostene 3,17 dione. These means involve dehydration at the9(11)-position, for example, with para-toluenesulfonic acid in refluxingbenzene. The 9(11) unsaturated compound is converted to a bromohydrin bytreatment with, for example, N-bromoacetamide. This 9-brorno compound isuseful in the preparation of other active compounds of this invention.The 9-bromo compound can be converted to 9-chloro, 9-fluoro or 9-iodocompounds by first treating the bromo compound with adehydrohalogenating agent such as potassium acetate in acetic acid toproduce a 9(11)-epoxide which, upon treatment with dride and catalyticamounts of potassium acetate.

hydrogen fluoride, chloride or iodide, is converted to the desired9-halo compound.

Various modifictions at the C position can be made by procedures wellknown in the art. For conversion of the 17-keto group to a 17-hydroxygroup the 3-keto group is preferentially converted to a pyrrolidinylderivative, the 17-keto group is then reduced with lithium aluminumhydride and the pyrrolidinyl group removed by refluxing in sodiumacetate-acetic acid bufiered aqueousmethanol solution. This reaction isdescribed in detail by Heyl and Herr in the Journal of The AmericanChemical Society, 75, 1918 (1953). The vinyl group can be introduced atthe C position by treating the 17-ketone with acetylenein the presenceof a potassium tert-alkoxide (for example, potassium tort-amyl oxide)and reducing the thus produced ethynyl group by catalytic hydrogenation.For the introduction of the vinyl group the 3-keto group should again beprotected by a pyrrolidinyl group which is, of course, subsequentlyremoved. The 17-keto group can be converted to a tertiary alcohol, thatis, an alkyl and hydroxyl group can be introduced at the 17- position bytreatment with an organo metallic compound of th type RLi or RMgXwherein R is alkyl up to four and X is a halogen. For the introductionof the vinyl group or the reaction with an organo-metallic compound the3-keto group should be protected by a pyrrolidinyl group as describedabove. A 17-hydroxyl group can be readily esterified with the usualesterifying agents if it is the hydroxyl group of a secondary alcohol.If it is the hydroxyl of a tertiary alcohol it can be esterified byrefluxing in a liqud anhydride, for example, acetic or propionicanhydride or in the case of a solid anhydride by heating the compound atabout C. in a hydrocarbon solvent solution such as xylene containing theanhy- Esters and acid esters of the 17-hydroxyl group can be obtained inthis manner. to a keto group by oxidation, for example, with chromicacid. If, however, there is a secondary hydroxyl group at the17-position it is best to acylate this group before oxidizing the groupat the ll-position. As stated above, all of these reactions areconventional in the art.

The valuable compounds of the instant invention are prepared from theabove described starting compounds in accordance with the method setforth in earlier filed patent applications, Serial No. 526,554, filedAugust 4, 1955, and Serial No. 633,538, filed January 10, 1957, of whichthe present application forms a continuation-in-part. The

earlier applications describe a method for the introduction of doublebonds into the 6(7)-position by dehydrogenation of a 3-keto-fi-dihydro-A-steroid compound with a quinone having an oxidation-reduction potentialless than 0.5 at a temperature of between 70 .C. and C. in an inertorganic solvent having a boiling point of at least about 70 C. Thesesolvents include mononuclear'aromatic hydrocarbons, mono-nuclearhalogenated aromatic hydrocarbon solvents, oxygenated polar alicyclicorganic solvents and oxygenated polar aliphatic organic solvents.Typical solvents include tertiary butanol, n-amyl alcohol, hexanol,isoamyl alcohol, heptanol 3, cyclohexanol, ortho dichlorobenzene,xylene, tertiary amyl alcohol, secondary amyl alcohol, benzene, toluene,acetic acid, propionic acid, butyric acid, butyl acetate, amyl acetate,hexyl acetate, butyl propionate, propyl propionate, and amyl propionate.The preparation of the valuable compounds of the instant invention usingthe process described in the earlier filed applications is more fullyillustrated in the appended examples.

Although the reactions with a quinone described above are applicable tocompounds in which the 17-position carries a free ,B-hydroxyl group, foroptimum results it is An 11 fi-hydroxyl group can be converted best thatthis hydroxyl group be acylated with an acyl hydrocarbon groupcontaining up to ten carbon atoms.

The term acyl hydrocarbon includes acyl hydrocarbon groups containingonly carbon, hydrogen and oxygen derived from monocarboxylic ordicarboxylic acids. In

the event that the acyl hydrocarbon group isorie derivedfrom adicarboxylic acid, it is often advantageous. to treat the isolatedanabolically active compounds with a base derived from an alkali metalor alkaline earth metal to prepare a metal salt. sodium, potassium,barium and calcium hydroxide as well, as the corresponding carbonatesand bicarbonates. ucts so prepared as especially useful because of theirincreased solubility in water.

The products of this invention, as stated above, are valuablemedicinally as anabolic agents, that is, they aid at rebuildinghumantissue injured by surgery or depleted by serious illness. When usedin the treatment of these conditions the compounds of this invention areadmin: istere din dosages of approximately the same order of magnitudeas other agents often recommended for these purposes such as17ot-ethyl-17-hydroxy-norandrosterone, 11 3,1713 hydroxy 9a fluoro 17ccmethyl 4 androstene 3 one or 11,8,171-3 dihydroxy 17a methyl -4-androstene-3-one. Because of their high order of activity it issometimes possible to use dosages of the compounds of this inventionwhich are lower than compounds presently utilized. They accomplish theirvaluable therapeutic effect with a minimum of undesirable androgenicactivity. For this reason, and because they are efiective at relativelylow levels, they can be administered for extended periods of time topatients of either.

sex.

The biologically active compounds of this invention maybe administeredalone or in combination with acceptable pharmaceutical carriers, thechoice of which is determined by the preferred route of administration,the solubility of the compound and standard pharmaceutical practice. Froraladministration the compounds may be, administered in the form oftablets containing excipients' such as starch or millt'sugar. Aqueoussolutions and elixirs which maybe sweetened or flavored may also beemployed. For intra-articular injection aqueous suspensions may beused.In this case various suspending and wetting agents may be added to thecomposition to obtain a suspension not tendingto settle out easily or topack down in the bottle in which it is stored. Intramuscular andsubcutaneous dosage forms may also beprepared by standard pharmaceuticalpractice.

The following examplesare given solely for the purpose of illustrationandare not to be. construed as limitations of this invention,manyapparent variations of which are possible without departingfromthespirit or scope thereof.

' 7 EXAMPLE I n -androstadiene-9a-flu0r0-I1 5,1 75-dihydroxy-3-one l 17-acemt e A mixture of 0.8 g. of A -androstene-9t-dihydroxy3- one17-acetate and 0.9 g. of chloranilin 70 ml. of tertbutanol was refluxedin a nitrogen atmosphere for eighteen hours. The reaction mixture wasthen diluted with 150 'ml. of chloroform. The solvent solution waswashedwith several small portions of sodium hydroxide solution Thesebases include, for example,

Prod.

' fluorine, bromine or iodine atoms.

benzoquinone in 35 ml. of n-amyl alcoholwas refluxedunder nitrogen withstirring for three hours. It was concentrated to 5 ml. on a hot plateand the solution taken up in 30 ml. of chloroform. It was washed twicewith 25 ml. portions of water, four times with 25 ml. portions of 5%aqueous sodiumhydroxide and four additional times with 25 ml. portionsofwater. The mixture was dried and concentrated to dryness in vacuo. Theresidue was ,triturated with 1:1' ether-ethyl acetate to give thedesiredproduct. I

This process was repeated to prepare analogous compounds in which the9a-chloro atom was replaced with It was repeated successfully to preparea variety of l7-csters including the acetate, .propionate, valerate andhexanoate. It was repeated using non-acylated l7-hydroxy compounds butthe yields were somewhat lower.

EXAMPLE Ill A -arzdrostadiene-9ot-fluoro-il 1 17-tri0ne A mixturecontaining 0.4 g. of A -androstene-9a-fluoro- 3,11,17-trione and 1.1 g.of 2,6-dichloro-1,4 benzoquinone in 35 ml. of ortho-dichlorobenzene wasrefluxed under nitrogen for three hours. It'was concentrated to 5 ml. ona hot plate and the residue taken up in 30 ml. of chloroform. It waswashed twice with 25 ml. portions of water, four times with 25 ml.portions of 5% sodium hydroxide and four additional times with 25 ml.portions of water. The organic layer was dried over anhydrous sodiumsulfate, filtered and concentrated to dryness in vacuo. The residue wastriturated with 1:1 ether-ethyl acetate to give the desired product.

The processed. was repeated to prepare analogous compounds in which thet-fill0l'0 atom was replaced with chlorine, bromine or iodine atoms.

EXAMPLE IV A mixture of 0.8 g. of A -norandrostene-9a-fiuoro-1la,-17/3-dihydroxy-17a-methyl-3-one l7-decanoate and 0.9 g. of chloranil in70 ml. of tert-butanol was refluxed in nitrogen atmosphere for eighteenhours. The solvent was removed in vacuo and the'residue taken up in ml.of chloroform. The chloroform solution was washed with several smallportions of 5% sodium hydroxide solution EXAMPLE V A-norzmdrostadiene-Qa-bromo-J 7B-hydroxy-1 7ot-n-butyl- 3,11-di0ne17-acetate A mixture containing 0.202 g. of A-norandrostene-9abromo-l7,8-hydroxy-l7a-n-butyl-dione 17-acetate, 0.324g. of 1,4-benzoquinone in 18 ml. of n-amyl alcohol was refluxed undernitrogen with stirring for three hours. It was concentrated to 5 m1. ona hot plate. and excess 1,4-benzoquinone liquor was taken up in-30 ml.of chloroforrnand the solution washed-twice with 25 cc. portions ofwater, four times with 25 cc. portions of 5% aqueous sodium hydroxideand four additional times with 25 ml. portions of water. The materialwas dried and concentrated to dryness in vacuo. Theresidue wastrituratcd with 1:1 ether-ethyl acetate to give the desired product.

The process was 'repeatedto prepare analogous compounds inWhiChIhBQzx-bTOmO atom was replaced with fluorine, chlorine or iodine.

EXAMPLE VI A -nrandr0stadiene-9u-flu0r0-3,1 1,1 7-trione A mixturecontaining 0.4 g. of A -norandrostene-9ufluoro-3,1l,l7-trione and 1.01g. of chloranil in 35 ml. of xylene was refluxed for twenty hours. Theresulting mixture was diluted with an equal volume of chloroform and thesolution washed first with an aqueous solution of sodium hydrosulfideand then with diluted aqueous sodium hydroxide and finally with water.The solution was dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo. The residue was triturated with ether to obtainthe desired product.

The process was repeated to prepare analogous compounds in which the9cc-flll01'0 atom was replaced with chlorine, bromine or iodine atoms.

EXAMPLE VII A -andr0stadiene-9a-chl0ro-11,8,17,9-dihydroxy-17avinyl-3-0ne 1 7-propionate A mixture containing 0.63 g. of A-androstene-9a-chloro-l1p,17,8-dihydroxy-l7a-vinyl-3-one l7-propionateand 0.98 g. of chloranil in 15 ml. of toluene was refluxed in a nitrogenatmosphere for twenty hours. The reaction mixture was diluted with 30ml. of chloroform, washed with several small portions of 5% sodiumhydroxide solution and then with water. It was dried over anhydroussodium sulfate, filtered and concentrated in vacuo. The residue wastriturated with ether to obtain the desired product.

The process was repeated to prepare analogous compounds in which the9a-chloro atom was replaced with fluorine, bromine or iodine atoms.

EXAMPLE VIII The procedure of Example II was repeated to prepare A-norandrostadiene 9oz fluoro-l7fl-hydroxy-3,1l-dione 17-acetate. It wasrepeated to prepare analogous compounds in which the 9afluoro atom wasreplaced with chlorine, bromine or iodine atoms.

EXAMPLE IX The free l7-a1cohols of the 17-esters prepared as in theprevious examples were each prepared by hydrolysis of the ester byaddition of one molar portion of potassium carbonate in 10%aqueous-methanol solution of the ester. The mixture was allowed to standat room temperature for one hour and then poured into iced water toprecipitate the free alcohols.

. EXAMPLE X A variety of esters of the 17-a1cohols synthesized in theprevious examples were prepared by treating each of the free alcoholswith acylating agents by conventional methods. These included suchcompounds as the formate, the propionate, the isobutyrate, thehexanoate, the benzoate, the octanoate, the stearate, the hemisuccimate,the tn'methyl acetate, the cyclohexane carbamate, the cyclopentylpropionate, etc. The acid esters of polycarboxylic esters such as thehemisuccinate have the advantage that the alkali metal or alkaline earthmetal salts can be prepared from them by treating with molar proportionsof a base such as sodium bicarbonate or calcium hydroxide. These saltsin addition to being biologically active have the advantage of beingmore soluble in water than the free alcohols themselves or the ordinaryesters thereof.

What is claimed is:

1. A compound selected from the group consisting of those having theformula:

wherein R is selected from the group consisting of hydrogen and CH R isselected from the group consisting of fl-hydroxyl and keto; X isselected from the group consisting of fluorine, chlorine, bromine andiodine; Z is selected from the group consisting of References Cited inthe file of this patent UNITED STATES PATENTS Murray Nov. 23, 1954Colton Mar. 27, 1956

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF THOSE HAVING THEFORMULA: